Descripción del proyecto
Estudiar los mecanismos de la autoinmunidad en la artritis reumatoide
Se calcula que el 1 % de la población mundial padece artritis reumatoide (AR), una enfermedad autoinmunitaria inflamatoria caracterizada por la presencia de autoanticuerpos (como los anticuerpos antipéptidos cíclicos citrulinados) y una inflamación grave que daña las articulaciones periféricas y añade una carga considerable a la vida del paciente. Por desgracia, aún se desconocen los mecanismos que causan el inicio de la inflamación tisular en la AR. Esto limita el éxito de su tratamiento y prevención. Para colmar esta laguna, el proyecto financiado con fondos europeos INSPIRE realizará un análisis espaciotemporal exhaustivo y en profundidad de la inflamación inducida por la autoinmunidad en la AR. Utilizará avances recientes como la secuenciación ATAC y de ARN de célula única junto con dextrámeros y antígenos del complejo principal de histocompatibilidad con códigos de barras de ADN, transcriptómica espacial e imágenes de vanguardia para explicar los mecanismos de la AR y permitir tratamientos novedosos.
Objetivo
Rheumatoid Arthritis (RA) is a prototypic T cell- and B cell-driven inflammatory autoimmune disease that affects around 1% of the population worldwide and creates a severe burden for patients as well as substantial socioeconomic costs for society. Hallmarks of RA are a destructive inflammation of peripheral joints as well as the presence of autoantibodies such as anti-citrullinated protein antibodies (ACPA). Although ACPA are considered to represent major drivers of RA pathology, they can be also found in otherwise healthy “individuals at risk” where they emerge decades before the eventual onset of RA. Factors and mechanisms that promote onset of tissue inflammation in such autoantibody-positive individuals still remain elusive. Due to this gap of knowledge, current therapies are primarily designed to suppress later stages of joint inflammation, rather than targeting the underlying processes of autoimmunity or the initial onset of inflammatory disease. RA patients thus still lack effective preventive or curative therapeutic concepts. Here we aim to exploit recent technical breakthroughs such as single-cell RNA- and ATAC-sequencing in conjunction with DNA bar-coded MHC dextramers and antigens, spatial transcriptomics and cutting-edge imaging to perform a comprehensive and in-depth spatiotemporal analysis of the molecular events underlying the initial onset of inflammatory disease in autoantibody-positive individuals. We will additionally profit from the access to a large and well-characterized cohort of ACPA-positive “individuals at risk” and ACPA-positive RA patients as well as from corresponding biomaterial. In combination with preclinical animal models of RA, we thereby seek to delineate the sequences of events that promote the early transition from autoimmunity to inflammation. The obtained data will yield key insights into basic mechanisms of inflammatory autoimmune diseases such as RA and provide the basis for novel treatment concepts.
Ámbito científico
- medical and health sciencesclinical medicinerheumatology
- medical and health scienceshealth sciencesinflammatory diseases
- medical and health sciencesbasic medicineimmunologyautoimmune diseases
- medical and health sciencesbasic medicinepathology
- engineering and technologyindustrial biotechnologybiomaterials
Palabras clave
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
10117 Berlin
Alemania